Stress-activated Map Kinases in Heart Failure

描述(由申请人提供)：心力衰竭是美国最重要的健康问题之一，缺血/心肌梗死是其主要原因之一。促炎基因，包括肿瘤坏死因子α、IL-6和COX2被高度诱导，并被认为在缺血/再灌注损伤后心力衰竭的病理失代偿中起作用。然而，介导它们在心肌细胞中诱导的信号机制还不是很清楚。在我们的初步研究中，我们发现应激激活的丝裂原活化蛋白(MAP)激酶p38的激活与缺血/再灌注密切相关。靶向激活p38活性可诱导心肌细胞中的促炎基因，并导致完整心脏的病理重塑。这些发现导致了我们目前的假设，即在缺血/心肌梗死期间，p38 MAP激酶的激活通过对心肌细胞中应激反应基因和炎症细胞因子的靶向调节而参与了心脏病理的特定方面。在这项提议中，我们将通过实现以下三个具体目标来严格检验这一假说：1)确定p38在体内调控炎症基因诱导和心脏重构中的功能作用。2).探讨p38通路在心肌梗死后炎症基因诱导和心脏损伤中的生理作用。3)确定p38在心肌细胞中功能和调控的分子基础。这些目标的实现将确立p38通路在缺血性心力衰竭中的功能意义，并为心力衰竭病理性重构的分子机制提供重要的新见解。更重要的是，它将为p38通路作为潜在的治疗心肌梗死和缺血性心力衰竭的新靶点提供关键信息。

DESCRIPTION (provided by applicant): Heart failure is one (1) of the most significant health issues in the US with ischemia/myocardial infarct as one (1) of its leading causes. Pro-inflammatory genes, including TNFalpha, IL-6 and COX2 are highly induced and thought to contribute to pathological decompensation in heart failure following ischemia/reperfusion injury. However, the signaling mechanism mediating their induction in cardiomyocytes is not yet well established. In our preliminary studies, we find that activation of stress-activated mitogen activated protein (MAP) kinase, p38 is highly correlated with ischemia/reperfusion. Targeted activation of p38 activities leads to induction of pro-inflammatory genes in cardiomyocytes and pathological remodeling in intact heart. These findings lead to our current hypothesis that p38 MAP kinase activation contributes to specific aspects of cardiac pathology during ischemia/myocardial infarction via targeted regulation of stress-response genes and inflammatory cytokine in cardiomyocytes. In this proposal, we will rigorously test this hypothesis by achieving the following 3 specific aims: 1) To determine the functional role of p38 in regulating inflammatory gene induction and cardiac remodeling in vivo. 2).To determine the physiological role of p38 pathway in inflammatory gene induction and cardiac injury following myocardial infarction. 3) To determine the molecular basis of p38 function and regulation in cardiomyocytes. Accomplishing these aims will establish the functional significance of p38 pathway in ischemic heart failure and add important new insight to the molecular mechanisms of pathological remodeling in failing heart. More importantly, it will provide critical information about p38 pathway as a potential new therapeutic target to treat myocardial infarction and ischemic heart failure.